Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms
  • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/10—Oxygen atoms

Definitions

• the present invention relates to an azulene derivative of a specific chemical formula and a salt thereof. More particularly, the present invention relates to an azulene derivative which effectively treats or prevents diabetes such as insulin-dependent diabetes (type 1 diabetes), and insulin-independent diabetes (type 2 diabetes), as well as various diabetes-related diseases such as insulin-resistant diseases and obesity, for example, as a pharmaceutical, particularly as a Na + -glucose cotransporter inhibitor, and to a salt thereof.
• diabetes such as insulin-dependent diabetes (type 1 diabetes), and insulin-independent diabetes (type 2 diabetes)
• various diabetes-related diseases such as insulin-resistant diseases and obesity
• a pharmaceutical particularly as a Na + -glucose cotransporter inhibitor
• a pharmaceutical to inhibit a Na + -glucose cotransporter (SGLT) in the intestinal tract and kidney to reabsorb glucose (a Na + -glucose cotransporter inhibitor) has been demanded as an antidiabetic agent to rapidly normalize hyperglycemia and improve the energy balance in the body.
• a Na + -glucose cotransporter inhibitor has been expected as an excellent pharmaceutical for treating or preventing diabetes such as insulin-dependent diabetes (type 1 diabetes) and insulin-independent diabetes (type 2 diabetes), as well as diabetes-related diseases such as insulin-resistant diseases and obesity.
• any of these compounds are an O-glycoside comprising an O-glucoside bond formed between glucose and an aglycon moiety, it has a problem that the hypoglycemic effect is disappeared due to hydrolysis of O-glucoside bond by glucosidase or the like in the small intestine when orally absorbed.
• Phloretin an aglycon moiety of phloridzin, is known to highly inhibit a facilitated diffusion-type glucose transporter. For example, it is reported that the cerebral glucose concentration decreases when phloretin is administered to the vein of a rat (e.g. Stroke, 1983, 14, 388). Phloretin is also known to inhibit a vitamin C transporter (Wang, Y. et al., Biochem. Biophys. Res. Commun., 2000, 267, 488-494).
• JP-A-2001-288178 (hereinafter referred to as Patent Document 1) describes that a compound of the following formula has the effect of inhibiting a Na + -glucose cotransporter and is useful as a treating agent or preventing agent for diabetes and a hypoglycemic agent.
• R 1 represents H, OH, lower alkyl group, -O-lower alkyl group, or the like
• R 2 represents H, -COO-lower alkyl group, or the like
• R 5 represents -CH 2 OH, -CH 2 OCOO-lower alkyl group, or the like
• a 1 represents pyridine, furan, thiophene, quinoline, indole, or the like
• n is 0, 1, 2, or 3
• m is 0 or 1 (See Patent Document 1 for further details on the symbols of the above formula).
• Patent Document 2 describes that a compound of the following formula can be used as the Na + -glucose cotransporter inhibitor to treat obesity or type 2 diabetes.
• R 1 , R 2 , and R 2a individually represent a hydrogen atom, OH, OR 5 , alkyl, CF 3 , OCHF 2 , OCHF 3 , or the like
• R 3 and R 4 individually represent a hydrogen atom, OH, OR 5a , -O-aryl, -O-CH 2 -aryl, alkyl, cycloalkyl, CF 3 , or the like
• A represents O, S, NH, or (CH 2 ) n , and n is 0, 1, 2, or 3 (See Patent Document 2 for further details on the symbols of the above formula).
• the C-glycoside is useful to a certain extent for treating diabetes due to the effect of inhibiting a Na + -glucose cotransporter.
• a compound having a chemical structure different from that of a known compound and showing the effect of inhibiting a Na + -glucose cotransporter more rapidly and more significantly has been increasingly desired for the clinical practice of diabetes treatment or the like.
• the present inventors have conducted extensive studies about a compound with a benzene ring directly bonded with a glucose residue and having the effect of inhibiting a Na + -glucose cotransporter.
• a compound (an azulene derivative) having an azulene ring bonded to a benzene ring directly or via a lower alkylene (-A-) which may be substituted with a halogen atom, with the benzene ring being directly bonded to a glucose residue shown by the following formula (I), has a significant effect of inhibiting a Na + -glucose cotransporter.
• the present invention provides a compound of the following formula (I) and a salt thereof (hereinafter both referred to as "compound of the present invention”).
• the compound of the present invention can be suitably used as a Na + -glucose cotransporter inhibitor using the compound as an active ingredient, particularly as a therapeutic agent and/or preventive agent for diabetes.
• a halogen atom, -OH, and -COOH are preferable as a substituent.
• the group represented by A of the above formula (I) is preferably a lower alkylene, and particularly preferably a methylene.
• the groups R 1 -R 4 of the above formula (I) are preferably a hydrogen atom.
• the azulene derivative of the above formula (I) may be preferably any one of compounds selected from the group consisting of 1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl] hexytol, 1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methoxyphenyl]hexytol, 1,5-anhydro-1-[3-(azulen-2-ylmethyl)-5-methoxyphenyl]hexytol, 1,5-anhydro-1-[3-(azulen-2-ylmethyl)-4-methoxyphenyl]hexytol, 1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-ethoxyphenyl]hexytol, 1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-methylphenyl]hexytol, 1,5-anhydro-1-[5-(azulen-2
• the present invention also provides a pharmaceutical composition containing the above azulene derivative or the salt thereof as an active ingredient and pharmaceutically acceptable adjuvants.
• the pharmaceutical composition of the present invention is effectively used for a Na + -glucose cotransporter inhibitor or a preventing agent or therapeutic agent for diabetes and diabetic complications.
• the present invention further provides use of the azulene derivative or the salt thereof for producing a Na + -glucose cotransporter inhibitor or a preventive agent and/or therapeutic agent for diabetes and diabetic complications.
• the present invention further provides a therapeutic method for diabetes and diabetic complications comprising administering an effective amount of the above azulene derivative or the salt thereof to a patient.
• lower refers to a linear or branched carbon chain having 1-6 carbon atoms, unless otherwise specified.
• examples of a “lower alkyl” include linear or branched alkyls having 1-6 carbon atoms such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, and isohexyl. Of these, alkyls having 1-3 carbon atoms are preferable, with a methyl and ethyl being particularly preferable.
• lower alkylene in addition to a methylene, ethylene, propylene, and butylene, a branched lower alkylene may be used. Of these, a methylene and ethylene are preferable, with a methylene being particularly preferable.
• halogen atom a fluorine atom, chlorine atom, bromine atom, or iodine atom can be given, with a chlorine atom and bromine atom being preferable.
• halogen-substituted lower alkyl or halogen-substituted lower alkylene a lower alkyl or lower alkylene substituted with the above halogen atom can be given, with a lower alkyl or lower alkylene substituted with one or more fluorine atoms being particularly preferable.
• aryl refers to a monocyclic to tricyclic aromatic hydrocarbon group having 6-14 carbon atoms.
• examples of the aryl include a phenyl, naphthyl, anthranyl, and phenanthryl, with a phenyl and naphthyl being particularly preferable.
• a "-lower alkylene-aryl” a benzyl and phenethyl are preferable.
• an acyl a formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, or the like can be given, with an acetyl being particularly preferable.
• -A- in the above formula (I) may be bonded to any one of the positions 1-8 of the azulene ring.
• the compound of the present invention includes a mixture or isolated product of various stereoisomers such as a tautomer and an optical isomer.
• the compound of the present invention may form an acid-addition salt or, depending on the type of substituent, a salt with a base.
• a salt include aid-addition salt with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; an acidic amino acid such as aspartic acid and glutamic acid; a salt of an inorganic base such as sodium, potassium, magnesium, calcium, and aluminum; an organic base such as methylamine, ethylamine, and ethanolamine; a basic amino acid such as lysine and ornithine; and ammonium salts.
• the compound of the present invention further includes hydrates and various pharmaceutically acceptable solvates and polymorphs.
• the compound of the present invention should not be limited to the compounds later described in examples, but includes all the compounds of the above formula (I) (azulene derivatives) and the pharmaceutically acceptable salts thereof.
• the compound of the present invention may includes any prodrug which is converted to any one of compounds of the above formula (I) or salts thereof in the body as a result of the metabolism in the body.
• a group for forming the prodrug of the compound of the present invention a group described in Prog. Med. 5: 2157-2161 (1985) or a group described in "Development of Pharmaceuticals," vol. 7, Molecular Design, 163-198 (Hirokawa Shoten, 1990) can be given. Therefore, the whole contents of those literatures are incorporated herein by reference.
• the compound of the present invention or the pharmaceutically acceptable salt thereof can be produced by various known synthesizing methods utilizing characteristics based on the type of its basic structure or substituent.
• a suitable protective group specifically, a group which can be readily converted to the functional group, at the stage of a starting material or intermediate, depending on the type of functional group.
• the protective group is optionally removed to obtain the target compound.
• a functional group include a hydroxyl group and carboxyl group.
• Examples of the protective group for these functional groups include protective groups described in Greene and Wuts, "Protective Groups in Organic Synthesis," Second Edition. These groups may be suitably used according to the reaction conditions.
• a process of Preparation Example 1 comprises subjecting an azulene compound (1) to a Friedel-Crafts reaction followed by reduction to prepare a compound (2), reacting the compound (2) with a compound (3) by an addition reaction to prepare a compound (4), reducing the compound (4) to prepare a compound (I), and deprotecting the compound (I) to prepare a compound (I'), as shown in the following formula. wherein R 1 to R 12 and A are the same as above.
• the Friedel-Crafts reaction is carried out in the presence of an appropriate Lewis acid, in the absence of a solvent, or in an appropriate solvent.
• the Lewis acid include aluminum chloride, boron trichloride, zinc chloride, vanadium chloride, ferric chloride, and stannic chloride.
• the solvent include ethers such as diethyl ether and tetrahydrofuran; haloalkyls such as chloroform, dichloromethane, and 1,2-dichloroethane; dimethylformamide; dimethylsulfoxide; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about 20°C to 180°C, and preferably about 20°C to 40°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent reduction reaction is carried out in the presence of an appropriate reducing agent and acid catalyst in a suitable solvent.
• the reducing agent include sodium borohydride, sodium cyanoborohydride, and lithium aluminum hydride.
• Specific examples of the acid include boron trifluoride-diethyl ether complex, trifluoroacetic acid, and trifluoromethanesulfonic acid.
• Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, and diglyme; haloalkyls such as chloroform, dichloromethane, and 1,2-dichloroethane; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about 0°C to 180°C, and preferably about 0°C to 60°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent addition reaction of the compound (2) to the compound (3) is carried out in the presence of an alkyl lithium reagent such as n-butyl lithium, sec-butyl lithium, or t-butyl lithium in a suitable solvent.
• an alkyl lithium reagent such as n-butyl lithium, sec-butyl lithium, or t-butyl lithium in a suitable solvent.
• the solvent include ethers such as diethyl ether, tetrahydrofuran, and diglyme.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about -80°C to 30°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the compound (4) may also be prepared by reacting the compound (2) with a Grignard reagent prepared using a metal reagent such as magnesium in a suitable solvent.
• a suitable solvent include ethers such as diethyl ether, tetrahydrofuran, and diglyme.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about 20°C to 180°C, and preferably about 20°C to 80°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like though.
• the subsequent reduction reaction is carried out in the presence of an appropriate reducing agent and acid catalyst in a suitable solvent.
• an appropriate reducing agent include triethylsilane, triisopropylsilane, and t-butyldimethylsilane.
• the acid catalyst include boron trifluoride-diethyl ether complex, trifluoroacetic acid, and trimethylsilyl trifluoromethanesulfonate.
• the solvent include haloalkyls such as chloroform, dichloromethane, and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran, and diglyme; acetonitrile; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about -40°C to 20°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the deprotection is carried out in the presence of a metal catalyst such as palladium/carbon, palladium hydroxide, or platinum/carbon in a suitable solvent in a hydrogen atmosphere, or in the presence of a Lewis acid in a suitable solvent.
• a metal catalyst such as palladium/carbon, palladium hydroxide, or platinum/carbon in a suitable solvent in a hydrogen atmosphere
• a Lewis acid include boron trichloride, boron tribromide, and aluminum trichloride.
• Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol and ethanol; acetonitrile; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about -80°C to 30°C, while it varies according to the type
• a process of Preparation Example 2 comprises reacting a compound (3) with a compound (5) to prepare a compound (6), reducing the compound (6) to prepare a compound (7), halogenating the compound (7) to prepare a compound (7'), reacting the compound (7') with an azulene derivative (8) to prepare a compound (I), and deprotecting the compound (I) to prepare a compound (I'), as shown in the following scheme.
• X represents a halogen, B(OR 13 ) 3 , wherein R 13 is H or a lower alkyl, or SnR 14 3 , wherein R 14 is a lower alkyl.
• reaction of the compound (3) with the compound (5) is carried out in the same manner as in the reaction of the compound (2) with the compound (3) of Preparation Example 1.
• the subsequent reduction reaction to prepare the compound (7) is carried out in the same manner as in the reduction reaction of the compound (4) of Preparation Example 1.
• the subsequent halogenation of the compound (7) to prepare the compound (7') is carried out in the presence of an appropriate halogenating agent in a suitable solvent.
• the halogenating agent include N-bromosuccinimide, bromine, hydrogen bromide.
• the solvent include haloalkyls such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate; ethers such as tetrahydrofuran and dioxane; dimethylsulfoxide; acetic acid; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent reaction of the compound (7') with the compound (8) is carried out in the presence of an appropriate palladium catalyst or in the presence of an appropriate palladium catalyst and an appropriate phosphine in a suitable solvent.
• the catalyst include tetrakistriphenylphosphine palladium (0), palladium acetate, bistriphenylphosphine dichloropalladium (II), 1,2-bis(diphenylphosphinoethane)dichloropalladium (II), 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (II), and tris(dibenzylideneacetone)dipalladium (0).
• the phosphine include trifurylphosphine, 2-(dicyclohexylphosphino)biphenyl, and tri(t-butyl)phosphine.
• the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme; alcohols such as methanol, ethanol, and isopropanol; benzene; toluene; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• This reaction may be carried out by reacting the compound (7') with a metal in a suitable solvent to prepare a metal reagent, and then reacting the reagent with the compound (8) in the presence of a palladium catalyst.
• a metal include copper, zinc, iron, and magnesium.
• the palladium catalyst, solvent, and reaction temperature are the same as above.
• the deprotection is carried out in the presence of an appropriate base in a suitable solvent.
• the base include sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide.
• Specific examples of the solvent include ethers such as tetrahydrofuran, dioxane, and diglyme; alcohols such as methanol, ethanol, and isopropanol; acetonitrile; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the deprotection is also carried out in the presence of an appropriate Lewis acid in a suitable solvent.
• the Lewis acid include boron trichloride, boron tribromide, and aluminum trichloride.
• Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol and ethanol; acetonitrile; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about -80°C to 60°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• a process of Preparation Example 3 comprises protecting an alcohol derivative (9), reacting the protected derivative (9) with a compound (3) to prepare a compound (10), reducing and deprotecting the compound (10) to prepare a compound (11), halogenating the compound (11) to prepare a compound (7'), reacting the compound (7') with an azulene derivative (8) to prepare a compound (I), and deprotecting the compound (I) to prepare a compound (I'), as shown in the following scheme.
• P represents a protective group
• X represents a halogen
• B(OR 13 ) 3 wherein R 13 is H or a lower alkyl, or SnR 14 3 , wherein R 14 is a lower alkyl.
• the alcohol derivative (9) is protected by a suitable protective group such as a t-butyldimethylsilyl group, t-butyldiphenylsilyl group, and tetrahydropyranyl group according to a conventional method.
• a suitable protective group such as a t-butyldimethylsilyl group, t-butyldiphenylsilyl group, and tetrahydropyranyl group according to a conventional method.
• the subsequent reaction with the compound (3) is carried out in the same manner as in the reaction of the compound (2) with the compound (3) of Preparation Example 1.
• the subsequent reduction reaction is carried out in the same manner as in the reduction reaction of the compound (4) of Preparation Example 1.
• the subsequent deprotection is carried out in the presence of an appropriate catalyst in a suitable solvent.
• the catalyst include tetrabutylammonium fluoride, boron trifluoride-diethyl ether complex, hydrogen fluoride, acetic acid, and p-toluenesulfonic acid.
• Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 20°C to 80°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent halogenation is carried out in the presence of a halogenating agent and triphenyl phosphine in a suitable solvent.
• a halogenating agent include N-bromosuccinmide, bromine, carbon tetrabromide, and copper (II) bromide.
• the solvent include haloalkyls such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate; ethers such as tetrahydrofuran and dioxane; benzene; toluene; dimethylsulfoxide; acetic acid; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• a process of Preparation Example 4 comprises reacting a bromobenzene derivative (12) with a compound (3) to prepare a compound (13), reducing the compound (13) to prepare a compound (14), converting the compound (14) to a trialkyltin derivative (15), reacting the derivative (15) with an azulene derivative (16) to prepare a compound (I), and deprotecting the compound (I) to prepare a compound (I'), as shown in the following scheme. wherein Y represents a halogen and R 15 represents a lower alkyl.
• the subsequent reduction reaction is carried out in the same manner as in the reduction reaction of the compound (4) of Preparation Example 1.
• the subsequent conversion to the trialkyltin derivative is carried out in the presence of hexaalkylditin and an appropriate palladium catalyst in a suitable solvent.
• the palladium catalyst include tetrakistriphenylphosphine palladium (0), palladium acetate, bistriphenylphosphine dichloropalladium (II), 1,2-bis(diphenylphosphinoethane)dichloropalladium (II), and 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (II).
• the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme; alcohols such as methanol, ethanol, and isopropanol; benzene; toluene; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent reaction with the azulene derivative (16) is carried out in the presence of an appropriate palladium catalyst or in the presence of an appropriate palladium catalyst and an appropriate phosphine in a suitable solvent.
• the catalyst include tetrakistriphenylphosphine palladium (0), palladium acetate, bistriphenylphosphine dichloropalladium (II), 1,2-bis(diphenylphosphinoethane) dichloropalladium (II), 1,1'-bis(diphenylphosphinoferrocene) dichloropalladium (II), and tris(dibenzylideneacetone) dipalladium (0).
• the phosphine include trifurylphosphine, 2-(dicyclohexylphosphino)biphenyl, and tri(t-butyl)phosphine.
• the solvent include ethers such as diethyl ether, tetrahydrofuran, dioxane, and diglyme; alcohols such as methanol, ethanol, and isopropanol; benzene; toluene; water; and a mixture of these solvents. The solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the deprotection is carried out in the same manner as in Preparation Example 2.
• a process of Preparation Example 5 comprises brominating a phenylacetic acid derivative (17) to prepare a compound (18), converting the compound (18) to a phenylacetone derivative (19), cyclizing the derivative (19) with a compound (20) to prepare a compound (2), reacting the compound (2) with a compound (3) to prepare a compound (4), reducing the compound (4) to prepare a compound (I), and deprotecting the compound (I) to prepare a compound (I'), as shown in the following scheme.
• the bromination of the phenylacetic acid derivative (17) is carried out in the presence of an appropriate brominating agent in a suitable solvent.
• the brominating agent include N-bromosuccinimide, bromine, hydrogen bromide.
• the solvent include haloalkyls such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate; ethers such as tetrahydrofuran and dioxane; dimethylsulfoxide; acetic acid; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 0°C to 100°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent derivation to the phenylacetone derivative (19) is carried out in the presence of an appropriate base in a suitable solvent.
• the base include sodium acetate, potassium acetate, and pyridine.
• Specific examples of the solvent include acetic anhydride.
• the reaction temperature is about -100°C to 180°C, and preferably about 30°C to 150°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the subsequent cyclization reaction is carried out by reacting the compound (19) with a suitable amine in the presence of an appropriate dehydrating agent in a suitable solvent and then reacting the mixture with the compound (20) in a suitable solvent.
• an appropriate dehydrating agent include morpholine, pyrrolidine, N-methylpiperazine, diethylamine, diisopropylamine.
• the dehydrating agent include magnesium sulfate and sodium sulfate.
• the solvent include ethers such as tetrahydrofuran, dioxane, and diethyl ether; haloalkyls such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate; alcohols such as methanol, ethanol, and isopropanol; benzene; toluene; acetonitrile; water; and a mixture of these solvents.
• the solvent is appropriately selected according to the type of reaction substrate or the reaction conditions.
• the reaction temperature is about -100°C to 180°C, and preferably about 20°C to 120°C, while it varies according to the type of starting material compounds, the reaction conditions, or the like within the above-mentioned range though.
• the reaction mixture was diluted with ethyl acetate.
• the diluted product was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.
• the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol (1.3 g).
• N-bromosuccinimide (1.7 g) and benzoyl peroxide (0.1 g) were added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol (3.7 g) in carbon tetrachloride (30.0 ml) and the mixture was refluxed with heating for one hour.
• the reaction mixture was diluted with chloroform and the diluted product was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium thiosulfate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.
• a catalytic amount of iodine was added to a suspension of metal magnesium (0.22 g) in THF (5.0 ml) in an argon atmosphere. Then, a solution of the compound in THF (5.0 ml) was added dropwise to the mixture, followed by refluxing with heating for one hour. The Grignard reagent thus prepared was added dropwise to a solution of 3-bromo-4-methylbenzaldehyde dimethylacetal (2.45 g) in THF (5.0 ml) at 0°C and the mixture was stirred for one hour. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate.
• Methyl iodide (0.17 ml) and potassium carbonate (0.4 g) were added to a solution of 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-tetrahydro-2H-pyran-2-yl]benzoic acid (1.5 g) in DMF (10 ml) at room temperature and the mixture was stirred for three hours. The insoluble matter was separated by filtration and the filtrate was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.
• Lithium aluminum hydride (73 mg) was added to a solution of methyl 4-methyl-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzoate (1.3 g) in THF (10 ml) at 0°C and the mixture was stirred for one hour. The reaction mixture was poured into ice-cooled water and the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.
• Reference Examples 35, 36, 37, 38, 39, and 40 were obtained respectively in the same manner as in Reference Example 26, Reference Example 3, Example 1, Reference Example 16, Reference Example 3, and Example 1.
• Reference Examples 42, 43, 44, 45, and 46 were obtained respectively in the same manner as in Example 37, Reference Example 32, Reference Example 41, Example 37, and Reference Example 32.
• the compound of Reference Example 48 was obtained in the same manner as in Reference Example 41.
• the compound of Reference Example 50 was obtained in the same manner as in Reference Example 32.
• Triphenylphosphine (0.66 g) was added to a solution of (6-isopropylazulen-2-yl)methanol (0.5 g) in carbon tetrachloride (10.0 ml) and the mixture was refluxed with heating for 15 hours. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-diethyl ether) to obtain 2-(chloromethyl)-6-isopropylazulene (0.38 g).
• the compound of Reference Example 53 was obtained in the same manner as in Reference Example 52.
• the reaction mixture was extracted with diethyl ether.
• the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The filtrate was concentrated and dried to be solid.
• the resulting residue was dissolved in dichloroethane (5 ml) and acetonitrile (25 ml).
• Triisopropylsilane (2.27 ml) and boron trifluoride-diethyl ether complex (0.85 ml) were added to the solution at -30°C. After stirring at the same temperature for 30 minutes, saturated aqueous solution of sodium bicarbonate was added to the reaction mixture.
• the mixture was extracted with diethyl ether.
• reaction mixture was cooled to room temperature and concentrated to the half amount, followed by adding methanol (25 ml) to the mixture and concentrating. This operation was repeated three times.
• the residue prepared by the concentration was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-[(3-methylazulen-1-yl)methyl]phenyl]-D-glucitol (0.068 g).
• Acetic anhydride (0.3 ml) was added to a solution of (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) in pyridine (5.0 ml) at room temperature and the mixture was stirred for 15 hours.
• the reaction mixture was diluted with ethyl acetate.
• the diluted solution was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated.
• Methyl 2-chloroazulene-1-carboxylate (0.35 g) and 1,1'-diphenylphosphinoferrocene dichloropalladium (II) (0.12 g) were further added to the mixture, followed by stirring at 50°C for two hours. After cooling to room temperature, the reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order and dried over anhydrous sodium sulfate. The reaction mixture was concentrated.
• Example 62 The compound of Example 62 was obtained in the same manner as in Example 39.
• a 1 M aqueous solution of sodium hydroxide (12 ml) was added dropwise to a solution of methyl 2- [3- [(1S)-1, 5-anhydro-D-glucitol-1-yl]-4-methoxy-1-naphthyl]methylazulene-1-carboxylate (0.23 g) in methanol (8.0 ml) and the mixture was refluxed with heating for three hours.
• a 1 M aqueous solution of hydrochloric acid (12 ml) was added to the reaction mixture under cooling with ice and the solvent was evaporated. The resulting residue was suspended in acetonitrile (15 ml).
• Tris(dibenzylideneacetone)dipalladium (0) (17 mg), 2-(dicyclohexylphosphino)biphenyl (22 mg), potassium fluoride (44 mg), and cesium carbonate (247 mg) were added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxy-3-methoxyphenyl]-D-glucitol (327 mg) and methyl 2-(tributylstanyl)azulene-1-carboxylate (180 mg) in 1,4-dioxane (10 ml). The mixture was vigorously stirred at 90°C for 14 hours.
• a 1 M aqueous solution of hydrochloric acid was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in THF (4 ml) and MeOH (2 ml), and a 1 M aqueous solution of sodium hydroxide (0.5 ml) was added to the reaction mixture at room temperature. After stirring for 30 minutes, a 1 M aqueous solution of sodium hydroxide (0.5 ml) was further added to the reaction mixture. The mixture was stirred for 30 minutes.
• Acetonitrile and a 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid (5 ml) were added to 2-[4-ethoxy-3-methoxy-5- [(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylic acid (50 mg) and the mixture was refluxed with heating for 10 minutes.
• a 4 M ethyl acetate solution (0.02 ml) of hydrochloric acid was further added to the reaction mixture and the mixture was refluxed with heating for 30 minutes. The reaction mixture was concentrated under reduced pressure.
• Tris(dibenzylideneacetone)dipalladium (0) (17 mg), 2-(dicyclohexylphosphino)biphenyl (22 mg), potassium fluoride (44 mg), and cesium carbonate (247 mg) were added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(bromomethyl)-2-fluorophenyl]-D-glucitol (198 mg) and methyl 2-(tributylstanyl)azulene-1-carboxylate (180 mg) in 1,4-dioxane (10 ml) and the mixture was vigorously stirred at 90°C for 15 hours.
• the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure.
• the resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane).
• the resulting residue (71 ml) was dissolved in THF-methanol (ratio: 1:1, 6.0 ml).
• Sodium methoxide (30 mg) was added to the solution and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure.
• Example 74 The compound of Example 74 was obtained in the same manner as in Reference Example 8.
• Rf refers to a number of Reference Example
• Ex refers to a number of Example
• Structure refers to a structural formula
• Ac refers to an acetyl group
• Bn refers to a benzyl group
• Bu refers to a butyl group
• Data refers to a property data
• NMR nuclear magnetic resonance spectrum (TMS internal standard)
• MS refers to a mass analysis value.
• the azulene derivative and the salt thereof have the effects of inhibiting a Na + -glucose cotransporter and reducing the level of blood glucose
• these compounds are useful for treating or preventing insulin-dependent diabetes (type 1 diabetes), insulin-independent diabetes (type 2 diabetes), insulin-resistant diseases, and obesity, for example, as a pharmaceutical, particularly as a Na + -glucose cotransporter inhibitor.
• single-strand cDNA was reversely transcripted from total RNA originating from the human kidney (manufactured by BD Biosciences Clontech) using a Superscript II (manufactured by Invitrogen Corporation) and a random hexamer.
• the amplified fragment was cloned into a pCR2.1-Topo vector using a Topo TA Cloning Kit (manufactured by Invitrogen Corporation) and the cloned vector was transfected into a competent cell of Escherichia coli JM109. Ampicillin-resistant clones were cultured in a LB medium containing ampicillin (100 mg/l). A plasmid was purified from the cultured Escherichia coli using the method of Hanahan (see Maniatis et al., "Molecular Cloning").
• a DNA fragment for encoding a human SGLT2 was obtained by the Hind III / EcoRI digestion of the plasmid and ligated and cloned to the same site of the expression vector pcDNA3.1 (manufactured by Invitrogen Corporation) using a DNA ligase (manufactured by Roche Diagnostics).
• the ligated clone was transfected into a competent cell of Escherichia coli JM109 in the same manner as described above and cultured in a LB medium containing ampicillin, and a human SGLT2 expression vector was obtained using the method of Hanahan.
• the human SGLT2 expression vector was transfected into a CHO-K1 cell using Lipofectamine2000 (manufactured by Invitrogen Corporation).
• the cell was cultured in a Ham' s F12 medium (manufactured by Nissui Pharmaceutical Co., Ltd.) containing penicillin (50 IU/ml, manufactured by Dainippon Pharmaceutical Co., Ltd.), streptomycin (50 ⁇ g/ml, manufactured by Dainippon Pharmaceutical Co., Ltd.), Geneticin (40 ⁇ g/ml, manufactured by Invitrogen Corporation), and 10% fetal bovine serum in the presence of 5% CO 2 at 37°C for two weeks, and Geneticin-resistant clones were obtained.
• a pretreatment buffer solution (buffer solution of pH 7.4 containing choline chloride (140 mM), potassium chloride (2 mM), calcium chloride (1 mM), magnesium chloride (1 mM), 2-[4-(2-hydroxyethyl)1-piperazinyl] ethanesulfonic acid (10 mM), and tris(hydroxymethyl) aminomethane (5 mM)) was added in the amount of 100 ⁇ l per well, and incubated at 37°C for 20 minutes.
• buffer solution of pH 7.4 containing choline chloride (140 mM), potassium chloride (2 mM), calcium chloride (1 mM), magnesium chloride (1 mM), 2-[4-(2-hydroxyethyl)1-piperazinyl] ethanesulfonic acid (10 mM), and tris(hydroxymethyl) aminomethane (5 mM) was added in the amount of 100 ⁇ l per well, and incubated at 37°C for 20 minutes.
• a buffer solution for intake containing a test compound buffer solution of pH 7.4 containing sodium chloride (140 mM), potassium chloride (2 mM), calcium chloride (1 mM), magnesium chloride (1 mM), methyl- ⁇ -D-glucopyranoside (50 ⁇ M), 2-[4-(2-hydroxyethyl)1-piperazinyl]ethanesulfonic acid (10 mM), and tris (hydroxymethyl) aminomethane (5 mM)
• a buffer solution for intake without a test compound was prepared for a control group.
• a buffer solution for basal intake without a test compound containing coline chloride (140 mM) instead of sodium chloride for measuring the basal intake was prepared as well.
• buffer solution for intake was added (25 ⁇ l per well) and incubated at 37°C for two hours.
• a buffer solution for washing buffer solution of pH 7.4 containing choline chloride (140 mM), potassium chloride (2 mM), calcium chloride (1 mM), magnesium chloride (1 mM), methyl- ⁇ -D-glucopyranoside (10 mM), 2-[4-(2-hydroxyethyl)1-piperazinyl]ethanesulfonic acid (10 mM), and tris(hydroxymethyl)aminomethane (5 mM) was added (200 ⁇ l per one well). The mixture was immediately removed. This washing operation was carried out once more.
• Fed KK-A y mice (CLEA Japan, Inc., male) were used.
• the test compound was suspended in 0.5% methylcellulose solution to a concentration of 3 mg/10 ml. The weight of each mouse was measured.
• the test compound suspension was orally administered forcibly to the mice at a dose of 10 ml/kg. Only 0. 5% methylcellulose solution was administered to the mice of a control group. Each group consisted of six mice. Blood was collected from the tail vein immediately before administering the compound and one, two, four, and eight hours after administering the compound. The blood glucose value was measured using a glucose CII Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.).
• the intensity of hypoglycemic activity was determined by calculating the area under the blood glucose value-time curve (AUC) using a trapezoidal method from the glucose value of 0-8 hours after administering the compound and calculating the rate (%) of the decrease in the AUC of the drug-administered group from that of the control group.
• AUC blood glucose value-time curve
• the compound of the present invention exhibited a strong hypoglycemic activity.
• the hypoglycemic activity of typical compounds of the present invention are shown in Table 25.
• the pharmaceutical composition containing one or more of the compounds of the present invention and the pharmaceutically acceptable salts thereof is prepared as a tablet, powder, fine granule, granule, capsule, pill, liquid, injection, suppository, ointment, adhesive, or the like using a carrier, vehicle, or other additives commonly used for preparation and is orally or nonorally administered.
• the amount of the compound of the present invention to be clinically administered to the human body is appropriately determined, taking the symptoms, weight, age, sex, and the like of a patient to which the compound is administered into consideration, in the range of 0.1-500 mg per day for oral administration or in the range of 0.01-100 mg per day for nonoral administration, once or several times a day. Since the amount to be administered varies according to various conditions, it may be sufficient to administer the compound at a smaller amount than the above-described amount.
• a tablet, powder, granule, or the like is used as a solid composition for oral administration of the compound of the present invention.
• one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystal cellulose, starch, polyvinylpyrrolidone, or magnesium aluminometasilicate.
• the composition may contain additives other than the inert diluent such as a lubricant such as magnesium stearate, a disintegrator such as carboxymethylcellulose calcium, and a solubilizer such as glutamic acid and aspartic acid by a conventional method.
• the tablet or pill may be optionally coated with a film of glucose or a stomach-soluble or intestines-soluble substance such as sucrose, gelatin, hydroxypropylcellulose, or hydroxypropylmethylcellulose phthalate.
• the liquid composition for oral administration includes pharmaceutically acceptable preparations such as an emulsion preparation, solution preparation, suspension preparation, syrup preparation, elixir preparation, and the like and contains a commonly used inert diluent such as purified water and ethyl alcohol.
• the composition may contain, in addition to the diluent, adjuvants such as a solubilizer, humectant, and suspending agent, sweetener, flavorer, perfume, and preservative.
• the injection for nonoral administration includes a sterilized aqueous or nonaqueous solution, suspension, and emulsion.
• the diluent for the aqueous solution or suspension include distilled water and a physiological saline solution for injection.
• the diluent for the nonaqueous solution or suspension include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil; alcohols such as ethyl alcohol; and Polysolvate 80 (trade name).
• Such a composition may further contain additives such as an isotonizing agent, preservative, humectant, emulsifier, dispersant, stabilizer (e.g. lactose), and solubilizer.
• These compounds are sterilized by filtering through a bacteria-retaining filter and adding a disinfectant or irradiating, for example. These compounds may be used by producing a sterilized solid composition and dissolving the composition in a sterilized water or injection solvent before using.

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